Project Summary/Abstract Peripheral artery disease (PAD) and small vessel disease (SVD) are the consequences of damage to the endothelial cells that line all vessels, both leading to inadequate skin perfusion and end-organ and limb damage. It is prevalent in diabetic patient population in which nearly 50% suffers from PAD and SVD. The proposed effort addresses an unmet need for early diagnosis of PAD and SVD in this high-risk group. A number of studies describe the difficulties in diagnosing arterial disease in diabetic patients, including the high risk of vascular calcification, which leads to overestimates of limb blood flow by ABI measurements and missed diagnosis of partial occlusions. Despite the important role of skin perfusion, it is seldom detected or even tested for in its early stages due to the lack of routine screening protocols and the requirement for expensive diagnostic equipment and trained technicians. This highlights the significant opportunity for development of a simple, inexpensive protocol to routinely screen subjects with skin perfusion risk factors early enough that would allow more effective treatment options for diabetic retinopathy, neuropathy, limb ischemia, cerebral vascular disease, coronary vascular disease and nephropathy. Creating a way to detect vascular disease at a point where changes are reversible will: 1) improve patient quality of life by delaying or preventing the development of end organ damage; and 2) decrease patient care costs. The proposed protocol utilizes hydrogen sulfide (H2S), a newly described endothelium-derived vasodilator that decreases with the onset of endothelial disease, the underlying cause of most PAD and SVD cases. Furthermore, normal levels of H2S are beneficial for preventing endothelial dysfunction, for improving recovery from muscle ischemia and in mitigating damage from myocardial infarction. There is currently no non-invasive method to accurately measure plasma H2S and the few existing techniques require specialized equipment and skilled technicians. Our proposed technology, the transdermal gasotransmitter sensor (TAGS?), employs an innovative gas-phase detector which noninvasively measures plasma levels of H2S. In the STTR Phase I feasibility study, the Exhalix and University of New Mexico team developed and used a laboratory version of TAGS to perform preliminary animal studies in which physiologically relevant normal and reduced plasma levels of H2S were transdermally detected in male Sprague-Dawley rats. During the proposed SBIR Phase II renewal studies, we intend to continue the development of advanced prototypes of TAGS. These prototypes will be verified and validated across a broad cross-section of subjects, including healthy and diabetic animal and human subjects of both sexes, in collaboration with experienced physician scientists at the School of Medicine and the Center for Translational and Clinical Sciences. We anticipate that successful development and validation of TAGS during Phase II will lead to Phase IIB clinical studies and commercialization of the technology.